Extracellular deposition of Aβ aggregates in the brain represents one of the defining pathologic features of AD (Price et al. (1995) Curr. Op. Neurol. 8:268; Selkoe (1999) Nature 399:A23; Yankner (1996) Neuron 16:921). Aβ is derived from proteolytic cleavage of APP, a type I transmembrane glycoprotein that belongs to a family of proteins that includes APP-like protein (APLP) 1 and 2. The processing of APP is initiated with the proteolysis of the extracellular/lumenal domain of the full length protein by either α- or β-secretase in the extracellular/lumenal domain, which leads to the generation of soluble N-terminal fragment sAPPα or sAPPβ and membrane anchored 83-residue or 99/89-residue membrane-bound C-terminal fragments (αCTF or βCTFs), respectively (De Strooper and Annaert (2000) J Cell Sci. 113:1857; Mattson (1997) Physiol. Rev. 77:1081; Younkin (1995) Ann. Neurol. 37:287). Subsequently, these fragments are cleaved by γ-secretase in the transmembrane region, resulting in the production of p3 (from αCTF) or the amyloidogenic peptides Aβ40 or Aβ42 (from βCTFs).
Cyclin-dependent kinase 5 (Cdk5) is a proline-directed protein kinase that phosphorylates serine and threonine residues. An interaction with either p35 or p39, two proteins abundantly expressed in post-mitotic neurons, is necessary for Cdk5 activation (Lew et al. (1994) Nature 371:423; Tang et al. (1995) J. Biol. Chem. 270:26897; Tsai et al. (1994) Nature 371:419). Cdk5 is a pleiotropic kinase that plays numerous functions in the mammalian central nervous system (Dhavan and Tsai (2001) Nat. Rev. Mol. Cell Biol. 2:749). The most well characterized role of Cdk5 is its involvement in the regulation of cortical development (Gupta et al. (2002) Nat. Rev. Genet. (2002) 3:342). Recent evidence also suggests the active participation of Cdk5 in axon guidance, dopamine signaling, and synaptic plasticity (Bibb et al. (2001) Nature 410:376; Bibb et al. (1999) Nature 402:669; Fischer et al. (2002) J. Neurosci. 22:3700; Ledda et al. (2002) Neuron 36:387; Li et al. (2001) Proc. Natl. Acad. Sci. USA 98:12742; Sasaki et al. (2002) Neuron 35:907).
Proteolytic cleavage of p35 generates p25, which leads to aberrant Cdk5 activation. Although p25 activates Cdk5, it is more stable and displays a different subcellular localization than p35. Conflicting reports exist as to whether p25 levels are increased in AD brains (Taniguchi et al. (2001) FEBS Lett. 489:46; Tseng et al. (2002) FEBS Lett. 523:58; Yoo and Lubec (2001) Nature 411:763). The accumulation of p25 is implicated in several neurodegenerative diseases. Current mouse models expressing p25, however, fail to effectively represent neurodegenerative phenotypes in vivo.